The overarching goal of the proposed studies is to understand better the effects of severe prenatal alcohol exposure on the structure and function of the developing human brain by using advanced image analysis technology to combine functional and structural magnetic resonance imaging (MRI) data. While severe prenatal exposure to alcohol is known to cause mental retardation and generalized microcephaly, little is yet known about the subtler toxic effects of prenatal alcohol exposure on brain structure and function. Recent structural MRI studies have shown brain shape abnormalities in parietal and anterior frontal brain regions in alcohol-exposed individuals that exceed their generalized microcephaly. One might expect brain functional activity to be altered in regions of brain structural abnormality, but to date, no functional MRI studies have been reported in the fetal alcohol syndrome (FAS) literature. In these proposed studies, we will assess differences in brain activation between children and adolescents with FAS and those who were not exposed to alcohol prenatally. We expect that regional patterns of functional abnormality will parallel regional patterns of structural abnormality. Advanced image analysis technology is required to address this issue when the groups to be compared have different brain shapes. Traditional functional image analysis techniques require brain image data to be scaled into standard space, typically by using automated procedures. Unfortunately, brain anatomy is less likely to be well matched with the automated algorithms in regions where brain shape differs between groups, greatly reducing the likelihood that subtle differences in brain function can be measured in these regions. We will address this problem by refining existing and developing new high-dimensional continuum mechanical image warping algorithms to align functional images of FAS and control subjects based on gyral landmarks identified in each individual's structural image data. We will design functional MRI experimental paradigms which have been shown to recruit both structurally "normal" and structurally "abnormal" brain regions to assess the specificity of alteration in brain function, and we will compare results from the more traditional and the novel spatial normalization procedures. The results of these studies will help us in planning intervention strategies to optimize development in FAS children and provide more optimal image analysis techniques for other pediatric populations.